Pyrimidine kinase inhibitors

ABSTRACT

Compounds that selectively inhibit inappropriate kinase activities and methods for their preparation are disclosed. In one embodiment, the compounds are represented by Formula I,  
                 
As selective inhibitors of inappropriate kinase activities, the compounds of the present invention are useful in the treatment of conditions associated with such activity, including, but not limited to, inflammatory and autoimmune responses, diabetes, asthma, psoriasis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. Also disclosed are methods of inhibiting inappropriate kinase activities and methods of treating conditions associated with such activities.

FIELD OF THE INVENTION

The invention relates to chemical compounds having kinase inhibitoryactivity and their use in the treatment of diseases and conditionsassociated with inappropriate kinase activity.

BACKGROUND OF THE INVENTION

Protein kinases are key elements in signal transduction pathwaysresponsible for transducing extracellular signals to the nuclei,triggering various biological events. [Schlessinger, J. and Ullrich, A.,“Growth factor signaling by receptor tyrosine kinases,” Neuron,9:383-391 (1992)] The many roles of protein tyrosine kinases (PTKs) innormal cell physiology include cell growth, differentiation, apoptosis,cell mobility and mitogenesis. [Plowman et al., “Receptor tyrosinekinases as targets for drug intervention,” DN&P, 7:334-339 (1994)].

Protein kinases include, for example, but are not limited to,extracellular signal-regulated kinases, p42/ERK² and p44/ERK1; c-JunNH₂-terminal kinase (JNK); cAMP-responsive element-binding proteinkinases (CREB); cAMP-dependent kinase (CAPK); mitogen-activated proteinkinase-activated protein kinase (MAPKAP); stress-activated proteinkinase p38/SAPK2; mitogen-and stress-activated kinase (MSK);p185^(neu)/Her-2/erbB-2; platelet derived growth factor receptor kinase(PDGFR); colony stimulating factor-1 receptor kinase (CSF1-R);endothelial growth factor receptor kinase (EGF-R); vascular endothelialgrowth factor kinase (VEGF-R); fibroblast growth factor receptor kinase(FGF-R); protein kinases, PKA, PKC and PKC-α; serine/threonine proteinkinase (STK); the Janus family of tyrosine protein kinases, JAK1, JAK2and JAK 3; human insulin receptor tyrosine kinase; the Src-family ofcytoplasmic PTKs, p60^(c-arc), c-Src, Hck, Fgr and Lyn; Abelson leukemiavirus PTK (c-Abl); p56^(fyn) (FYN); p56^(lck) (LCK); cyclin-dependentkinases (CDK1, CDK2, CDK3 and CDK4); NGF receptor kinase (Trk); Alkreceptor kinase; IKK-β kinase; Ax1/Ufo kinase; Rse/Sky kinase; Sykkinase; ZAP-70 kinase; NIK kinase; Yrk kinase; Fyk kinase; Blk kinase;Csk kinase; Tie-1 and Tie-2 kinase; TrkA, TrkB and Trk C kinases; andhuman growth factor kinase (HGF).

The disruption of the norrnal functions of kinases has been implicatedin many human diseases, including cancer, diabetes, restenosis,atherosclerosis, fibrosis of the liver and kidney and psoriasis. [Powis,G. and Workman, P., “Signaling targets for the development of cancerdrugs,” Anti-Cancer Drug Design, 9:263-277 (1994); Cantley et al.,“Oncogenes and signal transduction,” Cell, 64:281-302 (1991); Kolibaba,K. S. and Druker, B. J., “Protein tyrosine kinase and cancer,” BiochimBiophys Acta, 1333:F217-F248 (1997); Merenmies et al., “Receptortyrosine kinase signaling in vascular development,” Cell Growth Differ,8:3-10 (1997); Lavelle, F., “American Association for Cancer Research1997: Progress and New Hope in the Fight Against Cancer,” Exp OpinInvest Drugs, 6:771-775 (1997); and Shawver et al., “Receptor tyrosinekinases as targets for inhibition of angiogenesis,” Drug DiscoveryToday, 2:50-63 (1997)] In fact, about 30% of human breast and ovariancancer patients have exhibited increased expression of Her-2(p185^(neu)). [Plowman et al., “Receptor tyrosine kinases as targets fordrug intervention,” DN&P, 7:334-339 (1994)] Platelet-derived growthfactor receptor tyrosine kinases have been associated with humanmalignancies, arterial restenosis, and fibrosis of the liver, lung andkidney. Colony stimulating factor-1 receptor has been implicated in boneremodeling and hematopoiesis. Vascular endothelial growth factor (VEGF)is a homodimeric peptide growth factor which binds to two structurallyrelated tyrosine kinase receptors denoted Flt1 and KDR. [Waltenberger etal. (Ludwig Institute for Cancer Research, Uppsala Branch, Sweden),“Different signal transduction properties of KDR and Flt1, two receptorsfor vascular endothelial growth factor,” J. Biol. Chem., 269:26988-95(1994)]. VEGF receptor tyrosine kinases have been implicated in tumorangiogenesis, psoriasis, rheumatoid arthritis, atherosclerosis, andocular diseases. [Shawver et al., “Receptor tyrosine kinases as targetsfor inhibition of angiogenesis,” Drug Discovery Today, 2:50-63 (1997)]

Further examples of the role of inappropriate kinase activities invarious disease states and conditions include, but are not limited to,JAK2 kinase: myelo- and lymphoproliferative disorders [Science,278:1309-1312 (1997); Blood, 93:2369-2379 (1999)]; Fyn kinase: T-cellleukemia and lymphoma [Curr. Opin. Immunol., 6:372-379 (1994)]; Fgr, Lynand Hck kinases: rheumatoid arthritis and Crone's disease [J. Exper.Med., 185:1661-1670 (1997)]; Lck kinase: T-cell leukemia and lymphoma[Curr. Opin. Immunol., 6:372-379 (1994)]; Csk kinase: rheumatoidarthritis [J. Clin. Invest., 104:137-146 (1999)]; PKA and PKC kinases:diabetic complications such as blindness [Proc. N.Y. Acad. Sci.,89:11059 (1992)]; c-Abl kinase: chronic myelogenous leukemia [Blood,93:3973-3982 (1999); J. Cancer Res. Clin. Oncol, 124:643-660 (1998)];FGFR kinase: Crouzon syndrome, achondroplasia, thanatophoric dysplasia,leukemia, lymphoma and other autoimmune disorders [Nature Genetics, 8:98(1994); Cell, 78:335 (1994); Nature Genetics, 13:233 (1996)]; ERK1 andERK2 kinases: head and neck carcinoma [Br. J. Cancer, 80:1412-1419(1999)]; Tie-1 and Tie-2 kinases: breast cancer [Cancer Research,59:3185-3191 (1999); Br. J. Cancer,77:51-56 (1998)]; TrkA, TrkB and TrkCkinases: neuroblastoma [Clin. Cancer Res., 5:1491-1496 (1999)]; IKK-βkinase: inflammation and rheumatoid arthritis [Cell, 90:373-383 (1997);Nature, 388:548-554 (1997); Published PCT application WO 99/34000];MAPKAP kinase: inflammation and rheumatoid arthritis [Nat. Cell Biol.,1:94-97 (1999)]; p38/SAPK2 kinase: inflammation and rheumatoid arthritis[J. Bio. Chem., 274:19559-19564 (1999); Nature, 372:739-746 (1994); Ann.N.Y. Acad. Sci., 696:149-170 (1993)]; VEGFR kinase: melanoma, cancer,tumor angiogenesis, psoriasis, rheumatoid arthritis, atherosclerosis,ocular diseases and vascular disorders [Blood, 94:984-993 (1999);McMahon et al., “Protein kinase inhibitors: structural determinants fortarget specificity,” Drug Discovery & Development, 1:131-146 (1998)];HGF kinase: carcinoma and cancer [Int. J. Cancer, 82:449-458 (1999);Jikken Igaku, 16:2016-2025 (1998)]; p185^(neu)/Her-2 kinase: breastcancer [Nature, 385:540-544 (1997)]; NIK kinase: inflammation [Nature(London), 398:252-256 (1999)]; Ax1/Ufo kinase: myeloid leukemia andprostate cancer [Nature, 368:753-756 (1993); Cancer Detect. Prev.,23:325-332 (1999)]; Rse/Sky kinase: tumors and cell proliferation andbreast cancer [J. Biol. Chem., 270:6872-6880 (1995)]; c-Src kinase:colon and breast cancer [Biochem. Biophys. Res. Commun., 250:27-31(1998); Bone (Osaka), 10:135-144 (1996)]; NGF receptor kinase-Trk: coloncancer [Proc. Nat. Acad. Sci., 91:83-87 (1994); Proc. Nat. Acad. Sci.,84:2251-2253 (1987)]; PDGF kinase: chronic myelomonocytic leukemia,arteriosclerosis and fibrosis of the liver, lung and kidney [Oncogene,7:237-242 (1992); New Engl. J. Med., 314:488-500 (1986)]; Alk receptorkinase: lymphoma [Cell, 77:307-316 (1994); Blood, 93:3088-3095 (1999);Oncogene, 14:4035-4039 (1997)]; Syk kinase: anaplastic large celllymphoma [Science, 263:1281-1284 (1994); FEBS Lett., 427:139-143 (1998);J. Biol. Chem., 273:4035-4039 (1998)]; HRTK kinase: diabetes [Science,284:974-977 (1999); Diabetes, 38:1508 (1989)]; ZAP-70 kinase: immunedisorders [Curr. Biol., 9:203-206 (1999); EGFR kinase: carcinoma,psoriasis [Cancer Research, 57:4838-4848 (1997); Cell, 61:203-212(1990); J. Oncology, 4:277-296 (1994); U.S. Pat. No. 5,654,307 (Aug. 5,1997)]; JAK3 kinase: immune suppression, leukemia and organ transplantrejection [Adv. Immunology, 60:1-35 (1995); Leuk. Lymphoma, 32:289-297(1999)]; Science, 270:797-800 (1995)]; and CDK2 kinase: bladder cancer(Published PCT application WO97/16452).

Inappropriate protein kinase activities thus represent attractivetargets for therapeutic intervention and in fact, several small moleculekinase inhibitor compounds have been disclosed. Natural products such asstaurosporine, lavendustin A, erbstatin, genistein and flavopiridol forexample, have been shown to be effective kinase inhibitors. In addition,a number of synthetic tyrosine kinase inhibitors have also beenintroduced. [McMahon et al., “Protein kinase inhibitors: structuraldeterminants for target specificity,” Drug Discovery & Development,1:131-146 (1998)]. The present invention relates to novel compoundseffective as inhibitors of inappropriate kinase activities.

SUMMARY OF THE INVENTION

The compounds of the present invention are effective as inhibitors ofinappropriate kinase activities and therefore, are useful for theinhibition, prevention and suppression of various pathologies associatedwith such activities, such as, for example, inflammation, asthma,arthritis, diabetes, atherosclerosis, ocular diseases, restenosis,autoimmune responses, multiple sclerosis, psoriasis, human cancers,fibrosis of the liver, lung and kidney, transplantation rejection, andtumor metastasis.

Accordingly, in one embodiment, the present invention provides acompound, or a salt thereof, represented by Formula I:

wherein:

-   R¹ is chosen from —H, C₁ to C₂₀ hydrocarbon, aminocarbonylalkyl,    alkoxyalkyl, substituted arylalkyl, heteroaryl, heteroarylalkyl,    heterocyclylalkyl, and substituted heterocyclylalkyl;-   R² is chosen from halogen, C₁ to C₂₀ hydrocarbon, hydroxy,    heteroaryl, substituted heteroaryl, heterocyclyl, substituted    heterocyclyl,    wherein-   R⁵ is chosen from —H, alkyl and substituted alkyl;-   R⁶ is chosen from a direct bond, alkyl, aryl, substituted aryl and    heteroaryl; and-   R⁷ is chosen from —H, acyl, alkyl, substituted alkyl,    alkoxycarbonyl, amidine, aryl, arylalkyl, heterocyclyl, heteroaryl,    substituted heteroaryl, substituted aryloxy, heteroarylsulfonamido,    dialkylsulfonamido,    wherein-   R⁸ is chosen from —H and alkyl; and-   R⁹ is chosen from —H, alkyl, substituted alkyl, aryl, heteroaryl,    alkylcarbonyl and arylcarbonyl;-   R³ is chosen from a direct bond,    wherein the left hand bond is the point of attachment to the ring    and the right hand bond is the point of attachment to R⁴;-   R⁴ is chosen from —H, halogen, alkyl, heterocyclyl, alkylamino,    aminocarbonyl,    wherein-   R¹⁰ is chosen from —H, —OH, alkyl, cycloalkyl and substituted    cycloalkyl;-   R¹¹ is chosen from —H, —OH, —COOH, aryl, substituted aryl,    heteroaryl, substituted heteroaryl, aryl substituted alkyl,    cycloalkyl, substituted cycloalkyl, alkoxy, aminocarbonyl,    aminocarbonylalkyl,-   R¹² is chosen from alkyl and aryl;-   R¹³ is chosen from —H and aryl;-   R¹⁴ is chosen from aryl, substituted aryl, heteroaryl, substituted    alkyl, aryl substituted alkyl and alkoxy substituted alkyl,-   R¹⁵ is chosen from alkyl, aryl, substituted aryl and substituted    alkyl;-   R¹⁶ is chosen from aryl, substituted aryl, heteroaryl, carboxyl,    alkoxy, substituted alkyl, cycloalkyl, substituted cycloalkyl,    aminocarbonyl, substituted aminocarbonyl, heterocyclyl and-   R¹⁷ is chosen from alkyl and dialkylamino; and-   R¹⁸ is chosen from C₁ to C₂₀ hydrocarbon, substituted C₁ to C₂₀    hydrocarbon and heteroaryl;-   Y is chosen from —H and lower alkyl, or Y and R¹ taken together with    the attached N, may be chosen from heterocyclyl, substituted    heterocyclyl, heteroaryl and substituted heteroaryl; and-   wherein at least two of X, X¹ and X² are —N═, and the other is    chosen from —C(H)═ and —N═.

Compounds of Formula I thus include those wherein each of X, X¹ and X²is —N═ and those wherein two of X, X¹ and X² are —N═ and the other is—C(H)═.

Preferred compounds of Formula I, wherein each of X, X¹ and X² is —N═include:

A) Compounds wherein:

-   -   R¹ is chosen from C₁ to C₂₀ hydrocarbon and substituted        arylalkyl;    -   R² is        wherein        -   R⁵ and R⁷ are each —H and        -   R⁶ is chosen from substituted aryl and heteroaryl;    -   R³ is chosen from        and preferably, from    -   R⁴ is —C(O)NHR¹⁵ wherein        -   R¹⁵ is substituted aryl.

B) Compounds wherein:

-   -   R¹ is chosen from C₁ to C₂₀ hydrocarbon, aminocarbonylalkyl,        heteroarylalkyl and substituted arylalkyl;    -   R² is chosen from        wherein        -   R⁵ is chosen from —H and substituted alkyl; and        -   R⁷ is chosen from —H, —C(O)NR⁸R⁹, —C(NH)NR⁸R⁹ and —NR⁸R⁹            wherein            -   R⁸ is —H; and            -   R⁹ is chosen from —H, alkyl, aryl and arylcarbonyl;    -   R³ is chosen from        and preferably, from    -   R⁴ is —H.

C) Compounds wherein:

-   -   R² is        wherein        -   R⁵ is chosen from —H and alkyl; and        -   R⁷ is chosen from heterocyclyl, substituted heteroaryl, —H,            aryl, heteroaryl, substituted alkyl and —NR⁸R⁹ wherein            -   R⁸ is alkyl; and            -   R⁹ is substituted alkyl;    -   is chosen from        and preferably, from        and    -   R⁴ is chosen from —C(S)NHR¹², —C(O)NHR¹⁵ and —C(O)(CH₂)₀₋₂R¹⁶        wherein        -   R¹² is aryl;        -   R¹⁵ is substituted aryl; and        -   R¹⁶ is chosen from substituted aryl and heteroaryl.

D) Compounds wherein:

-   -   R¹ is chosen from C₁ to C₂₀ hydrocarbon, aminocarbonylalkyl,        substituted arylalkyl, heteroarylalkyl, heterocyclylalkyl, and        substituted heterocyclylalkyl;    -   R² is chosen from        wherein        -   R⁵ is —H; and        -   R⁷ is chosen from —H, heteroaryl, substituted heteroaryl,            and —NR⁸R⁹ wherein            -   R⁹ is chosen from alkyl carbonyl and substituted alkyl;    -   R³ is chosen from        and preferably, from        and    -   R⁴ is chosen from —H and —C(O)(CH₂)₀₋₂R^(16.)

E) Compounds wherein:

-   -   R¹ is chosen from C₁ to C₂₀ hydrocarbon, alkoxyalkyl,        substituted arylalkyl, heteroarylalkyl, and substituted        heterocyclylalkyl;    -   R² is chosen from        wherein        -   R⁵ is chosen from —H and alkyl; and        -   R⁷ is chosen from —H, heterocyclyl, substituted alkyl,            heteroarylsulfonamido, dialkylsulfonamido,            and —NR⁸R⁹ wherein            -   R⁹ is chosen from alkylcarbonyl, alkyl, substituted                alkyl, aryl and arylcarbonyl;    -   R³ is chosen from a direct bond,        and preferably, from    -   R⁴ is chosen from —H,        —C(S)NHR¹², —CHR¹³R¹⁴, —C(O)NHR¹⁵ and —C(O)(CH₂)₀₋₂R¹⁶ wherein        -   R¹⁰ is —H;        -   R¹¹ is —H;        -   R¹² is alkyl;        -   R¹³ is —H;        -   R¹⁴ is chosen from heteroaryl, substituted aryl and alkoxy            substituted alkyl;        -   R¹⁵ is chosen from aryl and substituted aryl; and        -   R¹⁶ is substituted aryl.

F) Compounds wherein:

-   -   R¹⁴ is chosen from aryl, substituted aryl, heteroaryl,        substituted alkyl and aryl substituted alkyl.

G) Compounds wherein:

-   -   R¹ is heteroaryl;    -   R² is chosen from halogen and    -   R³ is chosen from a direct bond,        preferably, from    -   R⁴ is chosen from —C(O)(CH₂)₀₋₂R¹⁶ and

The principles of the present invention also provide methods ofinhibiting inappropriate kinase activity in a mammal, wherein themethods comprise administering to the mammal an effective amount of acompound represented by Formula I, or a prodrug or salt thereof. As usedherein, inhibiting kinase activity is intended to include inhibiting,suppressing and preventing conditions associated with inappropriatekinase activity, including but not limited to, inflammation, asthma,arthritis, diabetes, atherosclerosis, ocular diseases, restenosis,autoimmune responses, multiple sclerosis, psoriasis, human cancers,fibrosis of the liver, lung and kidney, transplantation rejection, andtumor metastasis.

The principles of the present invention therefore also provide methodsof treating a disease or condition associated with inappropriate kinaseactivity. The methods comprise administering to a mammal in need of suchtreatment, an effective amount of a compound represented by Formula I,or a prodrug or salt thereof, to inhibit kinase activity, such that theactivity is regulated to treat, ameliorate or prevent the disease stateor condition associated with that kinase activity. Such conditionsinclude for example, but are not limited to, inflammatory and autoimmuneresponses, diabetes, asthma, arthritis, atherosclerosis, oculardiseases, restenosis, psoriasis, multiple sclerosis, human cancers,fibrosis of the liver, lung and kidney, inflammatory bowel disease,transplantation rejection, and tumor metastasis. As used herein,“treatment” of a mammal is intended to include prophylaxis andamelioration as well.

Accordingly, the compounds of the invention, as well as prodrugs orsalts thereof, may be used in the manufacture of a pharmaceuticalcomposition or medicament for the prophylactic or therapeutic treatmentof disease states in mammals. The compounds of the present invention maybe administered as pharmaceutical compositions as a monotherapy, or incombination with other therapeutic agents, such as, for example, otherantiinflammatory and/or immunosuppressive agents. Such other agents mayinclude, for example, antirheumatic, steroid, corticosteroid, NSAID,antipsoriatic, bronchodilator, antiasthmatic and antidiabetic agents.Combination therapies can involve the administration of thepharmaceuticals as a single dosage form or as multiple dosage formsadministered at the same time or at different times.

Any suitable route of administration may be employed for providing apatient with an effective amount of a compound of the present invention.Suitable routes of administration may include, for example, oral,rectal, nasal, buccal, parenteral (such as, intravenous, intrathecal,subcutaneous, intramuscular, intrasternal, intrahepatic, intralesional,intracranial, intra-articular, and intra-synovial), transdermal (suchas, for example, patches), and the like. Due to their ease ofadministration, oral dosage forms, such as, for example, tablets,troches, dispersions, suspensions, solutions, capsules, soft gelatincapsules, and the like, may be preferred. Administration may also be bycontrolled or sustained release means and delivery devices. Methods forthe preparation of such dosage forms are well known in the art.

Pharmaceutical compositions incorporating compounds of the presentinvention may include pharmaceutically acceptable carriers orexcipients, in addition to other therapeutic ingredients. Excipientssuch as starches, sugars, microcrystalline cellulose, diluents,lubricants, binders, coloring agents, flavoring agents, granulatingagents, disintegrating agents, and the like may be appropriate dependingupon the route of administration. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit forms. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

The compounds of the present invention may be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicbases, and hydrates thereof. Included among such base salts are ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations & Definitions

The following terms and abbreviations retain the indicated meaningthroughout this disclosure.

-   -   ATP=adenosine triphosphate    -   DCE=dichloroethylene    -   DCM=dichloromethane=methylene chloride=CH₂Cl₂    -   DIC=diisopropylcarbodiimide    -   DIEA=N,N-diisopropylethylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   DTT=dithiothreitol    -   EDTA=ethylenediaminetetraacetic acid    -   Fmoc=9-fluorenylmethoxycarbonyl    -   GST=glutathione S-transferase    -   HOBt=1-hydroxybenzotriazole    -   MES=2-(N-morpholino)ethanesulfonic acid    -   i-Pr₂NEt=diisopropylethylamine    -   Pr₂NEt=dipropylethylamine    -   TBS=t-butyldimethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran

“Alkyl” is intended to include linear or branched hydrocarbon structuresand combinations thereof of 1 to 20 carbons. “Lower alkyl” means alkylgroups of from 1 to about 10, preferably from 1 to about 8, and morepreferably, from 1 to about 6 carbon atoms. Examples of such radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.

“Aryl” means an aromatic hydrocarbon radical of 4 to about 16 carbonatoms, preferably of 6 to about 12 carbon atoms, and more preferably of6 to about 10 carbon atoms. The rings may optionally be substituted with1-3 substituents selected from alkyl, halogen, hydroxy, alkoxy, aryloxy,haloalkyl, phenyl and heteroaryl. Examples of aryl groups are phenyl,biphenyl, 3,4-dichlorophenyl and naphthyl.

“Arylalkyl” denotes a structure comprising an alkyl attached to an arylring. Examples include benzyl, phenethyl, 4-chlorobenzyl, and the like.

“Cycloalkyl” refers to saturated hydrocarbon ring structures of from 3to 12 carbon atoms, and preferably from 3 to 6 carbon atoms. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-methylcyclopropyl, cyclopropylmethyl, cyclopentylmethyl, norbomyl,adamantyl, pinanyl, myrtanyl and the like. “Lower cycloalkyl” refers tocycloalkyl of 3 to 6 carbons.

C₁ to C₂₀ hydrocarbon radicals include alkyl, cycloalkyl, alkenyl,alkynyl, aryl and combinations thereof. Examples include phenethyl,cyclohexylmethyl and naphthylethyl.

“Heterocyclyl” refers to a cyclic hydrocarbon structure of from 1 to 6,preferably 5 to 6, carbon atoms, and containing from 1 to 4 heteroatomschosen from O, N and S; or a bicyclic 9- to 10-membered heterocyclicsystem containing from 1 to 4 heteroatoms chosen from O, N and S.“Heteroaryl” refers to an unsaturated cyclic hydrocarbon structure offrom 1 to 6, preferably 5 to 6, carbon atoms, and containing from 1 to 4heteroatoms chosen from O, N and S; or a bicyclic 9- or 10-memberedheteroaromatic ring system containing 1-4 heteroatoms selected from O, Nand S. The methine H atoms of a heterocyclyl or heteroaryl structure maybe optionally substituted with alkyl, alkoxy or halogen. Examplesinclude: imidazole, pyridine, indole, thiophene, benzopyranone,thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline,pyrimidine, pyrazine, tetrazole, pyrazole, pyrrolyl, pyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl,3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl,piperazinyl, 1,3,5-triazinyl, 1,2,5-trithianyl, benzo(b)thiophenyl,benzimidazolyl, quinolinyl, and the like.

“Alkoxy” means a straight, branched or cyclic hydrocarbon configurationand combinations thereof, including from 1 to 20 carbon atoms,preferably from 1 to 8 carbon atoms, more preferably from 1 to about 4carbon atoms, and an oxygen atom at the point of attachment. Suitablealkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclohexyloxy, andthe like. “Lower alkoxy” refers to alkoxy groups having from 1 to 4carbon atoms.

“Alkenyl” refers to an unsaturated acyclic hydrocarbon radical in somuch as it contains at least one double bond. “Lower alkenyl” refers tosuch radicals containing from about 2 to about 10 carbon atoms,preferably from about 2 to about 8 carbon atoms and more preferably 2 toabout 6 carbon atoms. Examples of suitable alkenyl radicals includepropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl,3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and thelike.

“Alkynyl” refers to an unsaturated acyclic hydrocarbon radicalcontaining at least one triple bond. Examples include ethynyl, propynyl,and the like.

“Substituted alkyl” means an alkyl wherein at least one hydrogenattached to an aliphatic carbon is replaced with a substituent such asalkyl, amino, alkoxy, aryl, cyano, carboxyl, alkoxycarbonyl, halogen,alkylamino, alkyloxy, alkylcyano, acetyl, hydroxyl, alkylthio,alkylsulphonyl, carboxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl,haloalkyl, acylamino, dialkylamino, and nitro. Examples of suchsubstituent groups include cyano, methyl, isopropyl, methoxy, ethoxy,propoxy, amino, methylamino, phenyl, naphthyl, chlorine, fluorine, andthe like.

“Substituted cycloalkyl” means a cycloalkyl wherein at least onehydrogen attached to a ring carbon is replaced with a substituent suchas alkyl, amino, alkoxy, aryl, cyano, carboxyl, alkoxycarbonyl, halogen,alkylamino, alkyloxy, alkylcyano, acetyl, hydroxyl, alkylthio,alkylsulphonyl, carboxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl,haloalkyl, acylamino, dialkylamino, and nitro. Examples of suchsubstituent groups include cyano, methyl, isopropyl, methoxy, ethoxy,propoxy, amino, methylamino, phenyl, naphthyl, chlorine, fluorine, andthe like.

“Substituted aryl” means an aryl wherein at least one methine hydrogenattached to an aromatic carbon is replaced with a substituent such asalkyl, amino, alkoxy, aryl, acetamido, acetyl, cyano, carboxyl,alkoxycarbonyl, halogen, alkylamino, alkyloxy, alkylcyano, alkylthio,alkylsulphonyl, aminosulphonyl, carboxyalkyl, alkoxyalkyl,alkoxycarbonylalkyl, haloalkyl, acylamino, aminocarbonyl, dialkylamino,and nitro. Examples of such substituent groups include cyano, methyl,isopropyl, methoxy, ethoxy, propoxy, amino, methylamino, phenyl,naphthyl, chlorine, fluorine, and the like. Examples include arylamides, aryl carboxylic acids, aryl carboxylic acid esters, arylamidines, and the like, such as benzamide, benzoic acid, benzoic acidester, benzamidine derivatives and the like.

“Substituted heteroaryl” or “substituted heterocyclyl” means aheteroaryl or heterocyclyl optionally substituted with such substituentsas alkyl, amino, alkoxy, aryl, acetyl, cyano, oxo, carboxyl,alkoxycarbonyl, halogen, alkylamino, alkyloxy, alkylcyano, alkylthio,alkylsulphonyl, carboxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl,haloalkyl, acylamino, dialkylamino, and nitro. Examples of suchsubstituent groups include cyano, methyl, isopropyl, methoxy, ethoxy,propoxy, amino, methylamino, phenyl, naphthyl, chlorine, fluorine, andthe like.

“Substituted arylalkyl” means an arylalkyl optionally substituted withsuch substituents as alkyl, amino, alkoxy, aryl, acetyl, cyano,carboxyl, alkoxycarbonyl, halogen, alkylamino, alkyloxy, alkylcyano,alkylthio, alkylsulphonyl, aminosulphonyl, carboxyalkyl, alkoxyalkyl,alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, and nitro.Examples of such substituent groups include cyano, methyl, amino,isopropyl, methoxy, ethoxy, propoxy, methylamino, phenyl, naphthyl,chlorine, fluorine, and the like.

“Halogen” is intended to include for example, F, Cl, Br and I.

The term “prodrug” refers to a chemical compound that is converted to anactive agent by metabolic processes in vivo. [See, e.g., N. Boder and J.J. Kaminski, Ann. Rep. Med. Chem. 22:303 (1987) and H. Bundgarrd, Adv.Drug Delivery Rev., 3:39 (1989)]. With regard to the present invention,a prodrug of a compound of Formula I is intended to mean any compoundthat is converted to a compound of Formula I by metabolic processes invivo. The use of prodrugs of compounds of Formula I in any of themethods described herein is contemplated and is intended to be withinthe scope of the invention.

Terminology related to “protected,” “protecting” and/or “deprotecting”functionalities is used throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In this context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups” for the functionalities involved.

In the case of the present invention, the typical functionalities thatmust be protected are amines. Suitable groups for that purpose arediscussed in standard textbooks in the field of chemistry, such asProtective Groups in Organic Synthesis by T. W. Greene [John Wiley &Sons, New York, 1991], which is incorporated herein by reference.Particular attention is drawn to the chapter entitled “Protection forthe Amino Group” (pages 309-405). Preferred protecting groups includeBOC and Fmoc. Exemplary methods for protecting and deprotecting withthese groups are found in Greene and Wuts on pages 318 and 327.

The materials upon which the syntheses described herein are performedare referred to as solid supports, beads, and resins. These terms areintended to include: (a) beads, pellets, disks, fibers, gels, orparticles such as cellulose beads, pore-glass beads, silica gels,polystyrene beads optionally cross-linked with divinylbenzene andoptionally grafted with polyethylene glycol, poly-acrylamide beads,latex beads, dimethylacrylamide beads optionally cross-linked withN,N′-bis-acryloyl ethylene diamine, glass particles coated withhydrophobic polymer, etc., i.e., material having a rigid or semi-rigidsurface; and (b) soluble supports such as polyethylene glycol or lowmolecular weight, non-cross-linked polystyrene. The solid supports may,and usually do, have functional groups such as amino, hydroxy, carboxyl,or halo groups; where amino groups are the most common.

Tentagel™ NH₂ (Rapp Polymere, Tubingen, Germany) is a preferred aminefunctionalized polyethylene glycol-grafted polystyrene resin.Tentagel™-S-PHB resin has a para-hydroxy benzyl linker which can becleaved by the use of 90% trifluoroacetic acid in dichloromethane.Techniques for functionalizing the surface of solid phases are wellknown in the art. Attachment of lysine to the amino groups on a bead (toincrease the number of available sites) and subsequent attachment oflinkers as well as further steps in a typical combinatorial synthesisare described, for example, in PCT application WO95/30642, thedisclosure of which is incorporated herein by reference. In thesynthesis described in WO95/30642, the linker is a photolyticallycleavable linker, but the general principles of the use of a linker arewell illustrated.

Optical Isomers—Diastereomers—Geometric Isomers

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisometric forms which may be defined in terms of absolutestereochemistry as (R)- or (S)-, or as (D)- or (L)- for amino acids. Thepresent invention is meant to include all such possible diastereomers aswell as their racemic and optically pure forms. Optically active (R)-and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthonsor chiral reagents, or optically resolved using conventional techniques.When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended to include both (E)- and (Z)-geometric isomers. Likewise,all tautomeric forms are intended to be included.

The configuration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration; thus a carbon-carbon double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

In view of the above definitions, other chemical terms used throughoutthis application can be easily understood by those of skill in the art.Terms may be used alone or in any combination thereof. The preferred andmore preferred chain lengths of the radicals apply to all suchcombinations.

Utility

The compounds of the present invention have demonstrated utility asinhibitors of inappropriate kinase activity. The compounds shown inTable 1 have been synthesized according to the methods described hereinand have been tested in accordance with the protocols described below.All of the compounds shown exhibited kinase inhibition with an IC₅₀below 10 μM. Preferred compounds are those with an IC₅₀ below 5 μM. Morepreferred compounds are those with an IC₅₀ below 1 μM and most preferredare those with an IC₅₀ below 500 nM. These compounds are provided by wayof illustration only, and the invention is not intended to be limitedthereto.

Biological Assays Compound Preparation and Assay Format

Compounds were dissolved in dimethylsulfoxide as 10 mM stock solutions.For IC₅₀ determinations, serial dilutions were made at 20× the finalconcentration used in the assay. Assays were carried out in 96-wellU-bottom polypropylene microtiter plates.

Jak2 Assay—Casein Substrate/Filtermat Harvest

The final assay volume was 60 μl, prepared by first adding 3 μl of thetest compound to 27 μl of a solution containing 5 μM ATP, 10 nM[γ-³³P]ATP and 12 μM casein in assay buffer (20 mM Tris HCl, pH 8.0, 5mM MgCl₂, 1 mM EDTA and 1 mM DTT), followed by 30 μl of 20 nM GST-Jak2in assay buffer. The plate was mixed by shaking and then incubated atambient temperature for 45 min. and terminated by adding 5 μl of 0.5 MEDTA to each sample. The [γ-³³P]-incorporated casein is harvested onto aGF/C filtermat (see below) Final concentrations of assay components are:[ATP], 2.5 μM; [casein], 6 μM (10 μg/well); [Jak], 10 nM (˜34 ng/well).Staurosporine (1 μM) was used to determine background counts. This assaywould also be appropriate for Jak-3 inhibitory activity.

p38(SAPK2) or Erk1 Assay—Myelin Basic Protein/Filtermat Harvest

The assays are performed in V-bottomed 96-well plates. For both assays,the final assay volume is 60 μl prepared from three 20 μl additions ofenzyme, substrates [myelin basic protein (MBP) and ATP] and testcompounds in assay buffer (50 mM Tris pH 7.5, 10 mM MgCl₂, 50 mM NaCland 1 mM DTT). Bacterially expressed, activated p38 or Erk1 ispre-incubated with test compounds for 10 min. prior to initiation ofreaction with substrates. The reaction is incubated at 25° C. for 45min. and terminated by adding 5 μl of 0.5 M EDTA to each sample. The[γ-³³P]-incorporated MBP is harvested onto a GF/C filtermat (see below).The final concentration of reagents in the assays are ATP, 1 μM;[γ-³³P]ATP, 3 nM; MBP (bovine brain, Sigma catalog #M1891), 2 μg/well;activated p38, 10 nM; activated Erk1 (Upstate Biotechnology catalog#14-188), 2.5 μg/mL, 10 nM; DMSO, 0.3%.

IKK-β Assay—GST-IkappaBalpha(1-54)/Filtermat Harvest

The final assay volume is 60 μl prepared from three 20 μl additions of3× GST-IkappaBalpha(1-54) in assay buffer (20 mM HEPES pH 7.6, 5 mMMgCl₂, 50 mM NaCl, 1 mM EDTA and 1 mM DTT) plus test compound, followedby the addition of 3× baculovirus expressed IKK-β (S177E; S181E) inassay buffer which is incubated for 10 min prior to initiation ofreaction with a 3× ATP solution (6 μM ATP and 9 nM [γ-³³P] ATP). Thereaction is incubated at 37° C. for 30 min and terminated by harvestingonto a GF/C filtermat (see below). The final concentration of reagentsin the assay are ATP, 2 μM; [γ-³³P]ATP, 3 nM; GST-IkappaBalpha (1-54), 2μg/well; IKK-β], 5 nM; DMSO, 0.3%.

CDK4 Assay—GST-RbSE Substrate/Filter Harvest

The final assay volume is 50 μl prepared from two 25 μl additions of 2×GST-RbSE(768-928) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂, 2.5mM EDTA, 10 mM β-mercaptoethanol, 2 mM DTT), 20 μM ATP, 0.125 μCi[γ-³³P]ATP plus test compound, followed by the addition of 2×baculovirus expressed His₆-Cdk4/Cyclin D1 complex in assay buffer. Thereaction is incubated at ambient temperature for 45 min. and terminatedby addition of 50 μl of 250 mM EDTA followed by harvesting onto a GF/Cfiltermat (see below). The final concentration of reagents in the assayare ATP, 10 μM; [γ-³³P]ATP, 10 nM (0.125 uCi); GST-RbSE(768-928), 2.5μM; His₆-Cdk4/Cyclin D1 complex (10 μg per well); DMSO_(max), 2%.

CDK3 Assay—Histone H1 Substrate/Filter Harvest

The final assay volume is 50 μl prepared from two 25 μl additions of 2×Histone H1 in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂, 2.5 mMEDTA, 10 mM β-mercaptoethanol, 2 mM DTT), 20 μM ATP, 0.125 μCi[γ-³³P]ATP plus test compound, followed by the addition of 2×baculovirus expressed Cdk2/His₆-Cyclin E complex in assay buffer. Thereaction is incubated at ambient temperature for 45 min. and terminatedby addition of 50 μl of 250 mM EDTA followed by harvesting onto a GF/Cfiltermat (see below). The final concentration of reagents in the assayare ATP, 10 μM; [γ-³³P]ATP, 10 nM (0.125 μCi); Histone H1, 0.5 μM (1.0μg/well); Cdk2/His₆-Cyclin E complex, 10 nM; DMSO_(max), 2%.

Protein Kinase A Assay—Histone H1 Substrate/Filter Harvest

The final assay volume is 50 μl prepared from two 25 μl additions of 2×Histone (type III-SS) in assay buffer (40 mM Tris-HCl, pH 7.8,Mg(OAc)₂), 20 μM ATP, 0.02 μCi [γ-³²P]ATP plus test compound, followedby the addition of 2× baculovirus expressed Cdk2/ His₆-Cyclin E complexin assay buffer. The reaction is incubated at ambient temperature for 45min. and terminated quenching with 50 μl of 200 mM EDTA, 75 mMphosphoric acid followed by harvesting onto a GF/C filtermat (seebelow). The final concentration of reagents in the assay are ATP, 50 μM;[[γ-³²P]ATP, x nM (0.02 μCi), Histone, 2.4 μg/well; PKA, 10U (0.21 μg);DMSO_(max), 2%.

Src Assay—Zeta Chain Substrate/Plate Binding

The Src kinase assay is based on the phosphorylation of a recombinantHis₆-zeta chain substrate peptide adsorbed to a Costar 96-wellmicrotiter plate (EIA-RIA High Binding). (Alternatively, the His₆-zetachain can be adsorbed to a Xenopore Nickel plate. If background is aproblem, TBS supplemented with 0.02% Tween 20 can replace TBS.)

This assay is carried out in a 50 μl volume. Plates are first coatedwith 8-12 μg/well zeta chain in 100 μl per well TBS and allowed to standat 4° C. overnight, followed by a 3× wash with TBS. The plates areblocked using TBS, 1% BSA, 200 μl per well at ambient temperature for 1hr, followed by a 3× TBS wash. 25 μl of Src (100 ng/well) in assaybuffer (50 mM HEPES, pH 7.5 and 10 mM MgCl₂), followed by addition 25 μlof test compound and 20 μM ATP in assay buffer. The reaction is allowedto proceed for 45 min. at ambient temperature with shaking. The reactionis terminated by washing the plate 3× with TBS. Incorporated phosphateis determined by adding 5 ng/well anti-phosphotyrosine-Eu in 100 μl ofTBS, 1% BSA, 50 μM DPTA and incubating at ambient temperature withshaking for 1 hr. The plate is washed 6× with TBS followed by theaddition of 150 μl of enhancement buffer, shaken for 5 min. and measuredon a Victor time-resolved plate reader. The final concentration ofreagents in the plate are Src, 0.1U (100 ng); ATP, 10 μM; DMSO, 0.5%.

c-Abl Assay-Biotin Peptide Substrate/NeutrAvidin Plate Capture

The c-Abl kinase assay is based on the phosphorylation of a biotinylatedsubstrate peptide bound to a NeutrAvidin (Pierce, Rockville, Ill.)coated flat bottom polystyrene 96-well microtiter plate. Thephosphorylated peptide product is subsequently detected using aneuropium-labeled anti-phosphotyrosine antibody (Wallac Oy, Turku,Finland). Assay plates are made 24 hours in advance of the assay bycoating a Costar EIA/RIA plate with 50 μl of 2 μg/mL NeutrAvadin in TBSusing the a Tomtec liquid dispenser. The plate is allowed to stand for 2hours at ambient temperature or overnight at 4° C. The plate is washed3× with TBS, 0.1% Tween-20 (TBST). Using the Tomtec liquid dispenser,the plate is next coated with 40 μl of 100 nM Abl biotinylated substratepeptide (Glu-Ala-Ile-Tyr-Ala-Ala-Pro-Phe-Ala-Lys(ε-biotin)-NH₂) in TBS,1.0% BSA. The plate is allowed to stand for 2 hours at ambienttemperature or up to 1 week at 4° C., and then washed 3× with TBST.

The assay is carried out by the addition of 20 μl of test compound inassay buffer to the assay plate followed by addition of 40 μl of amixture of c-Abl, ATP and anti-pY-Eu in assay buffer. The finalconcentrations of reagents per well in solution are c-abl, 3U; ATP, 2μM; anti-pY-Eu, 0.1 μg/mL. The plate is vortexed lightly for 5 min. andthe reaction is allowed to proceed for 1 hr. at ambient temperature. Thereaction is quenched by washing 3× with TBST. Europium counts aremeasured following the addition of 100 μl Enhancement solution (Wallac)per well on a Victor time-resolved plate reader (Wallac).

VEGF Kinase Assay

This assay may be used to detect VEGF binding. VEGF is a peptide growthfactor that binds to two structurally related tyrosine kinase receptors,Flt1 and KDR. Cultured human umbilical vein endothelial (HUVE) cellsexpress two distinct populations of binding sites with affinitiessimilar to those for Flt1 and KDR, respectively. The KDR expressingcells show striking changes in cell morphology, actin reorganization andmembrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation,whereas Flt1 expressing cells lack such responses. KDR undergoesligand-induced autophosphorylation in intact cells, and both Flt1 andKDR are phosphorylated in vitro in response to VEGF, however, KDR muchmore efficiently than Flt1. [Waltenberger J. et al. (Ludwig Institutefor Cancer Research, Uppsala Branch, Sweden), “Different signaltransduction properties of KDR and Flt1, two receptors for vascularendothelial growth factor,” J. Biol. Chem., 269:26988-95 (1994)]

Zap-70 Kinase Assay

The assay is performed in black 384-well plates at a final volume of 20μl. The bacterial expressed cytoplasmic domain of human erythrocyte band3 (cdb3) is used as a protein substrate for Zap-70 kinase. The assayplates are coated with cdb3 (10 μg/mL) at 4° C. overnight, and washedwith TBS once. 10 μl of test compounds in kinase buffer (25 mM MES,pH6.7, 10 mM MnCl₂, 0.1% BSA and 2 μM ATP) is added to each well,followed by the addition of 10 μl diluted activated Zap-70 to initiatethe reaction. The final concentration of reagents in the assays are ATP,1 μM; MES_(pH 6.7), 25 mM; MnCl₂, 10 mM; BSA, 0.1%; DMSO, 1%. Afterincubation at 25° C. for 45 min., reaction solution is removed, and theplates are washed 3× with TBS. 20 μl of europium-labeledanti-phosphotyrosine antibody (Wallac catalog # CR03-100) at 0.25 μg/mLis added to each well. The plates are incubated at 25° C. for 1 hr withcontinuous shaking. The plates are washed 5 times with TBS before 25 μlof enhancement solution is added to each well. The time-resolvedfluorescence is measured using a Victor reader (Wallac).

Reaction Termination by Filtration Harvesting and Data Analysis

After the designated time, the reaction mixture was aspirated onto apre-wet filtermat using a Skatron Micro96 Cell Harvester (Skatron,Inc.), then washed with PBS. The filtermat is then dried in a microwaveoven for 1 min., treated with MeltilLex A scintillation wax (Wallac Oy,Turku, Finland), and counted on a Microbeta scintillation counter Model1450 (Wallac). Inhibition data were analyzed by nonlinear least-squaresregression using Prizm (GraphPad Software).

Methods of Synthesis

General methods of synthesis for compounds of the present invention areillustrated by the following examples. The specific embodiments arepresented by way of illustration only, and the invention is not to belimited thereto. Modifications and variations in any given material orprocess step will be readily apparent to one of skill in the art and areintended to be included within the scope of the invention.Solution Phase Synthesis of Phenyl Amino Triazines

To a solution of cyanuric chloride (1.84 g; 10 mmol) in acetone (15 mL)at 0° C. was added 2-chloroaniline (1.28 g; 10 mmol) and 3.3 mL of 3 MNaOH (aq) (10 mmol). The mixture was stirred at 0° C. for 2 hr. Theresultant thick slurry was poured into ice-cold water (approx. 40 mL)and filtered to collect the product as an off white solid. The solidproduct was then washed with cold H₂O (2×) and cold ethanol (2×) anddried to afford 2.06 g of crude triazine 1 (75% yield) which wassuitable for use without further purification. Data for 1: ¹H NMR(d₆-DMSO, 300 MHz) 11.00 (s, 1H), 7.70-7.20 (m, 4H).

To a solution of cyanuric chloride (1.84 g; 10 mmol) in acetone (15 mL)at 0° C. was added 3-aminobenzamide (1.36 g; 10 mmol) and 3.3 mL of 3 MNaOH (aq) (10 mmol). The mixture was stirred at 0° C. for 2 hr. Theresultant thick slurry was poured into ice-cold water (approx. 40 mL)and filtered to collect the product as an off-white solid. The solidproduct was then washed with cold H₂O (2×) and cold ethanol (2×) anddried to afford 2.75 g of crude triazine 2 (80% yield) which wassuitable for use without further purification. Data for 2: ¹H NMR(d₆-DMSO, 300 MHz) 11.21 (s, 1H), 8.02 (s, 1H), 7.78 (d, 1H), 7.69(d,1H), 7.45 (t, 1H).

Derivatization of Resin with bis-Fmoc-Lysine

The resin loading was effectively doubled by initial derivatization withbis-Fmoc-lysine using the following procedure. To a suspension of 10.12g of ArgoGel (0.42 mmol/g, 4.25 mmol, 1.00 eq) in CH₂Cl₂ (100 mL) in alarge shaking vessel (200 mL capacity) was added bis-Fmoc-lysine (10.04g, 17.00 mmol, 4 eq), DIC (2.66 mL, 17.00 mmol, 4 eq), and HOBt (2.30 g,17.00 mmol, 4 eq). The resulting resin suspension was then shaken for 2hr at 25° C. The resin was washed with DMF (5×) and CH₂Cl₂ (5×) anddried in vacuo. The resulting bis-Fmoc-lysine derivatized resin 3 gave anegative result with both the ninhydrin and bromophenol blue tests(tests for primary amine and basic amine functionality).

Fmoc Deprotection of bis-Fmoc-Lysine Derivatized Resin

To 12.55 g (0.68 mmol/g, 8.53 mmol, 1.00 ed) of bis-Fmoc-lysinederivatized resin 3 in a large shaking vessel was added 100 mL of a 30%v/v solution of piperidine in DMF. The resulting suspension was shakenfor 1 hr at 25° C. The resin was washed with DMF (5×) and CH₂Cl₂ (5×).The resin-bound deprotected lysine gave a positive result with both theninhydrin and bromophenol blue tests.

Acylation with the Acid Cleavable Linker

To 11.08 g (0.77 mmol/g, 8.53 mmol, 1.00 eq) of the resin-bounddeprotected lysine in CH₂Cl₂ (100 mL) was added the acid cleavablelinker (8.13 g, 34.12 mmol, 4 eq), DIC (5.34 mL, 34.12 mmol, 4 eq), andHOBt (4.61 g, 34.12 mmol, 4 eq). The resulting suspension was shakenovernight at 25° C. The resin was washed with DMF (5×) and CH₂Cl₂ (5×)and dried in vacuo. The resulting resin-bound product 4 gave a negativetest with both the ninhydrin and bromophenol blue tests.

Preparation of Triazine 8:

First Combinatorial Step—Reductive Amination with a Primary Amine

To 300 mg (0.59 mmol/g, 0.177 mmol, 1.00 eq) of the resin-boundo-methoxybenzaldehyde 4 in DCE (10 mL) was added(S)-(+)-cyclohexylethylamine (0.184 mL, 1.24 mmol, 7 eq) and NaHB(OAc)₃(188 mg, 0.885 mmol, 5 eq). The resulting suspension was shaken for 14hr at 25° C. The resin was washed with DMF (5×) and CH₂Cl₂ (5×) and thendried in vacuo. The resulting resin-bound secondary amine 5 gave apositive result with the bromophenol blue test.

Second Combinatorial Step—Alkylation with Phenylaminotriazine 1

To 320 mg (0.55 mmol/g, 0.176 mmol, 1.00 eq) of resin-bound secondaryamine 5 in triglyme (10 mL) was added the triazine 1 (122 mg, 0.44 mmol,2.5 eq) and 0.154 mL of i-Pr₂NEt. The resulting suspension was heated to80° C. overnight. The suspension was then filtered and the resin washedwith DMF (5×) and CH₂Cl₂ (5×). This was used without drying.

Third Step—Addition of Secondary Amine (thiomorpholine)

To 362 mg (0.49 mmol/g, 0.177 mmol, 1.00 eq) of resin-boundchlorotriazine 6 in triglyme (4 mL) was added thiomorpholine (1 mL). Theresulting suspension was heated to 80° C. overnight. The suspension wasfiltered and the resin washed with DMF (5×) and CH₂Cl₂ (5×) and thendried in vacuo.

Acid Cleavage of Resin-Bound Trisubstituted Triazine 7

To 319 mg (0.47 mmol/g, 0.150 mmol) of resin-bound triazine 7 was added10 mL of a 1:1 solution of TFA/CH₂Cl₂. The resulting mixture was stirredfor 2 hr at 25° C. and then filtered. The filtrate was concentrated invacuo and the residue was purified by flash column chromatography (SiO₂,elution with 3:1 hexanes:EtOAc) giving 45 mg of pure trisubstitutedtriazine 8.

Data for 8: MS: m/z (relative intensity) 433.3 (M⁺, 100), 435.3 (M⁺+2,32).

Preparation of Triazine 10: First Combinatorial Step—Reductive Aminationwith a Primary Amine

To 300 mg (0.59 mmol/g, 0.177 mmol, 1.00 eq) of the resin-boundo-methoxybenzaldehyde 4 in DCE (10 mL) was added(S)-(+)-cyclohexylethylamine (0.184 mL, 1.24 mmol, 7 eq) and NaHB(OAc)₃(188 mg, 0.885 mmol, 5 eq). The resulting suspension was shaken overniteat 25° C. The resin was washed with DMF (5×) and CH₂Cl₂ (5×) and thendried in vacuo. The resulting resin-bound secondary amine 5 gave apositive result with the bromophenol blue test.

Second Combinatorial Step—Alkylation with Phenylaminotriazine 2

To 320 mg (0.55 mmol/g, 0.176 mmol, 1.00 eq) of resin-bound secondaryamine 5 in triglyme (10 mL) was added the triazine 2 (120 mg, 0.44 mmol,2.5 eq) and 0.154 mL of i-Pr₂NEt. The resulting suspension was heated to80° C. in an oven overnight. The suspension was then filtered and theresin washed with DMF (5×) and CH₂Cl₂ (5×). This was used withoutdrying.

Third Step—Addition of Primary Amine (1-(3-aminopropyl)imidazole)

To 364 mg (0.49 mmol/g, 0.178 mmol, 1.00 eq) of resin-boundchlorotriazine 9 in triglyme (4 mL) was added 1-(3-aminopropyl)imidazole(1 mL). The suspension was heated to 80° C. in an oven overnight. Thesuspension was filtered and the resin washed with DMF (5×) and CH₂Cl₂(5×). This was then dried in vacuo.

Acid Cleavage of Resin-Bound Trisubstituted Triazine 10

To 131 mg (0.47 mmol/g, 0.062 mmol) of resin-bound triazine 10 was added10 mL of a 1:1 solution of TFA/CH₂Cl₂. The resulting mixture was stirredfor 2 hr at 25° C. and then filtered. The filtrate was concentrated invacuo and the residue was purified by flash column chromatography (SiO₂,elution with 10% methanol in methylene chloride) giving 8 mg of puretrisubstituted triazine 11. Data for 11: MS: m/z (relative intensity)464.3 (M⁺+1, 100).

To 1.0 g of magnesium turnings in 15 mL dry ethyl ether was added aniodine crystal and cyclohexylethyl bromide (0.95 g, 5.0 mmol). After 30minutes the cloudy mixture was transferred to a solution of cyanuricchloride (0.92 g, 5.0 mmol) in 10 mL dry THF. After 2 hr the mixture wasconcentrated, taken up in DCM and washed with saturated NaHCO₃ andbrine. The organic layer was dried over MgSO₄. Filtration and removal ofvolatiles under reduced pressure gave 12 as an oil. (0.88 g, 3.4 mmol,68%, M+H⁺=261)

To 12 (0.42 g, 1.6 mmol) in 20 mL acetone was added 6-aminobenzothiazole(0.29 g, 1.9 mmol) and stirred at room temperature for 1 hr. The mixturewas concentrated, taken up in DCM and washed with saturated NaHCO₃ andbrine. The organic layer was dried over MgSO₄. Filtration and removal ofvolatiles under reduced pressure gave 13 as a solid. (0.022 g, 0.06mmol, 4%, M+H⁺=374).

To 13 (0.022 g, 0.06 mmol) in 3 mL DCM was added 100 mg of piperazineand stirred at room temperature for 3 hr. The mixture was concentrated,dissolved in DCM and washed with saturated NaHCO₃ and brine. The organiclayer was dried over MgSO₄. Filtration and removal of volatiles underreduced pressure gave 14 as a solid. (0.013 g, 0.03 mmol, 50%, M+H⁺=424)

To (1R)-(−)-Myrentol in 10 mL THF was added methylamine (2.0M in THF,7.5 mL), then NaHB(OAc)₃ and stirred at room temperature overnight. Themixture was then concentrated, dissolved in DCM and washed withsaturated NaHCO₃. The organic layer was extracted into 1N HCl and washedtwice with DCM. The aqueous layer was adjusted to pH 12 with 3N NaOH andextracted with DCM. The combined organic layers were dried over MgSO₄.Filtration followed by removal of volatiles under reduced pressure gave15 as an oil (0.43 g, 2.6 mol, 26%, M+H⁺=166)

0.26 g (1.6 mmol) of 15 was taken up in 15 mL EtOH and placed in a Parrhydrogenation apparatus with 50 mg of 10% Pd/C and shaken at 50 psi for6 hr. The solution was filtered through Celite and concentrated. Theresulting oil was taken up in DCM and washed with saturated NaHCO₃ andbrine. The organic layer was dried over MgSO₄. Filtration and removal ofvolatiles under reduced pressure gave 16 as an oil. (0.13 g, 0.75 mmol,46%, M+H⁺=168)

Compound 16 (0.05 g, 0.3 mmol) was combined with 17 (0.09 g, 0.2 mmol)and DIEA (53 μL, 0.3 mmol) in 5 mL DMF and heated to 60° C. overnight.The mixture was then concentrated, taken up in DCM and washed withsaturated KHSO₄, saturated NaHCO₃, and brine. The organic layer wasconcentrated to yield 18 as a foam. (0.055 g, 0.09 mmol, 32%, M+H⁺=579).

16 mL (100 mmol) of (1R)-(−)-Myrentol was taken up in 50 mL ethanol. Tothis was added 25 mg of platinum oxide and placed on a Parr hydrogenatorat 50 psi overnight. The mixture was then filtered through Celite andconcentrated under reduced pressure to yield 19 as an oil. (15.0 g, 97mmol, 97%, M+H⁺=155)

To NaH (0.52 g, 13 mmol) in 30 mL dry THF was added 19 (1.5 g, 10 mmol)in 10 mL dry THF slowly. After 10 minutes, cyanuric chloride (1.8 g, 10mmol) in 10 mL dry THF was added slowly. The reaction mixture wasstirred at room temperature overnight. Water (5 mL) was slowly added tothe mixture. The mixture was then concentrated, dissolved in DCM andwashed with saturated NaHCO₃ and brine. The organic layer was dried overMgSO₄. Filtration and removal of volatiles under reduced pressure gave20 as an oil. (0.64 g, 2.1 mmol, 21%, M+H⁺=303)

To NaH (0.07 g, 1.72 mmol) in 10 mL dry THF was added dropwise asolution of 6-aminobenzo thiazole (0.20 g, 1.33 mmol) in 5 mL dry THF.After 10 minutes, 20 (0.44 g, 1.46 mmol) in 5 mL dry THF was addeddropwise. The reaction mixture was stirred at room temperature for 2 h,after which 5 mL of water was added slowly. The mixture was thenconcentrated, dissolved in DCM and washed with saturated NaHCO₃ andbrine. The organic layer was dried over MgSO₄. Filtration and removal ofvolatiles under reduced pressure gave 21 as a solid. (0.45 g, 1.1 mmol,83%, M+H⁺=416)

Compounds of Formula I wherein two of X, X¹ and X² are —N═ and the otheris —C(H)═ may be synthesized as follows:

Scheme 1 illustrates a solution phase synthesis via chloropyrimidinesand Scheme 2 illustrates a solution phase synthesis viafluoropyrimidines. As shown in Scheme 1, 390 mg of the free amine 22(1.1 mmol) is treated with 0.6 mL of i-Pr₂NEt and 500 mg6-imidazolyl-2,4-dichloropyrimidine (2.0 mmol) in DMF at 50° C. for 16hr, then diluted with ethyl acetate and washed with saturated NH₄Cl,H₂O, brine, dried over MgSO₄ and concentrated and purification by flashchromatography (eluted with 8:10:1 EtOAc Hexanes: MeOH) to give 23 and24.

92 mg of 23 (0.21 mmol) in 3 mL of n-butanol is treated with 0.9 mL of3-chlorobenzylamine and 1 mL of i-Pr₂NEt at 100° C. for 16 hr, thencooled to room temperature, diluted with ethyl acetate and washed withsaturated NH₄Cl, H₂O, brine, dried over MgSO₄ and concentrated. Thecrude product is purified by flash chromatography (eluted with 4:5:1EtOAc:Hexanes:MeOH) to give 25.

Alternatively, as illustrated in Scheme 2, 280 mg of the free amine 22(1.1 mmol) is treated with 0.25 mL of i-Pr₂NEt and 200 mg of6-imidazolyl-2,4-difluoropyrimidine (1.1 mmol) in THF at roomtemperature for 13 hr, then diluted with ethyl acetate and washed withsaturated NH₄Cl, H₂O, brine, dried over MgSO₄ and concentrated. Thecrude product is purified by flash chromatography (eluted with 8:10:1EtOAc:hexanes:MeOH) to give 26 (less polar product) and 27 (more polarproduct). Four hundred fifty milligrams of 27 (1.08 mmol) in 50 mL ofTHF or n-butanol is then treated with 1.7 g of 3-chlorobenzyl amine and5 mL of i-Pr₂NEt at 80° C. for 16 hr then diluted with ethyl acetate andwashed with saturated NH₄Cl, H₂O, brine, dried over MgSO₄ andconcentrated. The crude product is purified by flash chromatography(eluted with 6:12:1 EtOAc:hexanes:MeOH) to give 28.

2-amino-1-methylbenzimidazole (5.15 g, 35 mmol) was added to a solutionof trifluoro pyrimidine (4.40 g, 32.8 mmol) and iPr₂NEt (5.9 mL, 34mmol) in CH₂Cl₂. After 16 hr, the reaction mixture was concentrated toapproximately 30 mL. The two regioisomers, 2-(2-amino-1-methylbenzimidazole)-4,6-difluoropyrimidine 29 and 4-(2-amino-1-methylbenzimidazole)-2,6-difluoro pyrimidine 30 were separated by silica gelchromatography (50-100% ethyl acetate in toluene). 2.04 g (23%) of the4-substituted regioisomer and 2.17 g (25%) of the 2-substitutedregioisomer were isolated.

2-(2-amino-1-methylbenzimidazole)-4,6-difluoropyrimidine (29)

¹H NMR (CDCl₃, 300 MHz) δ8.38, d, 1H; 8.23 bs 7.22, dd 1H; 7.06, dd, 1H;6.88, d, 1H; 6.38, s, 1H; 3.42, s, 3H.

¹⁹F NMR (CDCl₃, 75 MHz) 39574 Hz.

4-(2-amino-1-methylbenzimidazole)-2,6-difluoropyrimidine (30)

¹H NMR (CDCl₃, 300 MHz) δ8.65, bs, 1H; 8.40, bs, 1H; 7.04-7.22,m, 3H;6.87, d, 1H; 3.31, s, 3H.

¹⁹F NMR (CDCl₃, 75 MHz) 42596 Hz, 38829 Hz.

To 500 mg (0.55 mmol/g, 0.275 mmol) of resin-bound secondary amine 5 intriglyme (10 mL) was added 29 (143 mg, 0.55 mmol) and 0.154 mL ofi-Pr₂NEt (175 μL, 1 mmol). The resulting suspension was heated to 80° C.for 16 hr. The suspension was then filtered and the resin washed withDMF (5×) and CH₂Cl₂ (5×). Bromophenol blue test was negative indicatingcomplete reaction of the resin-bound secondary amine.

To 450 mg (0.248 mmol) of resin-bound fluoropyrimidine in DMSO (4 mL)was added 1-(3-aminopropyl)imidazole (1 mL). The suspension was heatedto 100° C. for 16 hr. The suspension was filtered and the resin washedwith DMF (5×) and CH₂Cl₂ (5×). This was then dried in vacuo.

To 400 mg (0.21 mmol) of resin-bound trisubstituted pyrimidine was added5 mL of a 1:1 solution of TFA/CH₂Cl₂. The resulting mixture was stirredfor 2 hr at 25° C. and then filtered. The filtrate was concentrated invacuo and the residue was purified by flash column chromatography (SiO₂,elution with ethyl acetate) to give the pure trisubstituted pyrimidine31. Data for 31: MS: m/z (relative intensity) 473.4 (M⁺+1, 100).

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of general principles,and the invention is not necessarily limited thereto. Modifications andvariations in any given material or process step will be readilyapparent to those skilled in the art without departing from the truespirit and scope of the following claims, and all such modifications areincluded within the scope of the present invention. TABLE 1 MW

534.63

578.73

577.75

564.70

466.65

566.72

544.63

420.49

432.50

448.59

448.59

548.66

421.52

396.90

383.47

456.52

416.52

362.45

424.45

524.52

560.69

460.62

489.42

462.61

440.50

473.70

448.56

506.67

548.64

463.64

463.64

520.69

478.66

578.73

424.57

506.67

556.75

524.64

415.94

578.73

480.63

394.88

536.69

535.71

423.58

414.96

464.63

466.65

480.67

394.88

444.56

520.69

400.93

404.53

422.59

305.79

396.90

414.96

410.92

546.73

460.60

464.63

450.60

445.58

377.00

391.00

405.00

392.00

420.00

422.93

472.61

553.71

565.72

569.75

550.68

516.66

580.70

586.75

540.64

587.81

517.65

532.70

602.79

556.68

431.34

398.87

406.51

383.51

383.51

393.47

399.42

419.55

460.60

329.37

409.53

354.45

331.80

395.50

340.42

381.47

488.61

518.64

551.67

544.67

531.68

595.79

488.61

504.65

534.68

567.71

560.71

533.69

547.72

611.83

603.85

504.65

500.62

528.67

530.65

598.76

552.65

563.68

556.68

529.66

543.69

607.80

500.62

439.97

410.92

446.57

405.52

419.55

460.60

389.26

355.46

394.88

515.03

482.95

488.6

463.52

491.53

523.6

548.64

546.7

410.94

449.55

470.41

449.57

448.57

578.77

464.63

544.63

423.54

423.54

489.38

596.75

566.72

359.45

626.77

645.61

478.00

1. A compound, or a salt thereof, represented by Formula I,

wherein: R¹ is chosen from —H, C₁ to C₂₀ hydrocarbon,aminocarbonylalkyl, alkoxyalkyl, substituted arylalkyl, heteroaryl,heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;R² is chosen from halogen, C₁ to C₂₀ hydrocarbon, hydroxy, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl,

wherein R⁵ is chosen from —H, alkyl and substituted alkyl; R⁶ is chosenfrom a direct bond, alkyl, aryl, and heteroaryl; and R⁷ is chosen from—H, acyl, alkyl, substituted alkyl, alkoxycarbonyl, amidine, aryl,arylalkyl, heterocyclyl, heteroaryl, substituted heteroaryl, substitutedaryloxy, heteroarylsulfonamido, dialkylsulfonamido,

wherein R⁸ is chosen from —H and alkyl; and R⁹ is chosen from —H alkyl,substituted alkyl, aryl, heteroaryl, alkylcarbonyl and arylcarbonyl; R³is chosen from a direct bond,

wherein the left hand bond is the point of attachment to the ring andthe right hand bond is the point of attachment to R⁴; R⁴ is chosen from—H, halogen, alkyl, heterocyclyl, alkylamino, aminocarbonyl,

wherein R¹⁰ is chosen from —H, —OH, alkyl, cycloalkyl and substitutedcycloalkyl; R¹¹ is chosen from alkyl, —H, —OH, —COOH, aryl, heteroaryl,substituted heteroaryl, aryl substituted alkyl, cycloalkyl, substitutedcycloalkyl, alkoxy, aminocarbonyl, aminocarbonylalkyl,

R¹² is chosen from alkyl and aryl; R¹³ is chosen from —H and aryl; R¹⁴is chosen from aryl, substituted aryl, heteroaryl, substituted alkyl,aryl substituted alkyl and alkoxy substituted alkyl; R¹⁵ is chosen from—H, alkyl, aryl, substituted aryl and substituted alkyl; R¹⁶ is chosenfrom aryl, substituted aryl, heteroaryl, carboxyl, alkoxy, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aminocarbonyl, substitutedaminocarbonyl, heterocyclyl and

R¹⁷ is chosen from alkyl and dialkylamino; and R¹⁸ is chosen from C₁ toC₂₀ hydrocarbon, substituted C₁ to C₂₀ hydrocarbon and heteroaryl; Y ischosen from —H and lower alkyl, or Y and R¹ taken together with theattached N, may be chosen from heterocyclyl, substituted heterocyclyl,heteroaryl and substituted heteroaryl; and wherein two of X, X¹ and X²are —N═, and the other is —C(H)═. 2-3. (canceled)
 4. A compound, or saltthereof, according to claim 1, wherein: R¹ is chosen from C₁ to C₂₀hydrocarbon and substituted arylalkyl; R² is

wherein R⁵ and R⁷ are each —H and R⁶ is chosen from substituted aryl andheteroaryl; R³ is chosen from

and R⁴ is —C(O)NHR¹⁵, wherein R¹⁵ is substituted aryl.
 5. A compound, orsalt thereof, according to claim 1, wherein: R¹ is chosen from C₁ to C₂₀hydrocarbon, aminocarbonylalkyl, heteroarylalkyl and substitutedarylalkyl; R² is chosen from

wherein R⁵ is chosen from —H and substituted alkyl; and R⁷ is chosenfrom —H, —C(O)NR⁸R⁹, —C(NH)NR⁸R⁹ and —NR⁸R⁹ wherein R⁸ is —H; and R⁹ ischosen from —H, alkyl, aryl and arylcarbonyl; R³ is chosen from

R⁴ is —H.
 6. A compound, or salt thereof, according to claim 1, wherein:R² is

R⁵ is chosen from —H and alkyl; and R⁷ is chosen from heterocyclyl,substituted heteroaryl, —H, aryl, heteroaryl, substituted alkyl and—NR⁸R⁹ wherein R⁸ is alkyl; and R⁹ is substituted alkyl; R³ is chosenfrom

R⁴ is chosen from —C(S)NHR¹², —C(O)NHR¹⁵ and —C(O)(CH₂)₀₋₂R¹⁶ whereinR¹² is aryl; R¹⁵ is substituted aryl; and R¹⁶ is chosen from substitutedaryl and heteroaryl.
 7. A compound, or salt thereof, according to claim1, wherein: R¹ is chosen from C₁ to C₂₀ hydrocarbon, aminocarbonylalkyl,substituted arylalkyl, heteroarylalkyl, heterocyclylalkyl, andsubstituted heterocyclylalkyl; R² is chosen from

wherein R⁵ is —H; and R⁷ is chosen from —H, heteroaryl, substitutedheteroaryl, and —NR⁸R⁹ wherein R⁹ is chosen from alkyl carbonyl andsubstituted alkyl; R³ is chosen from

R⁴ is chosen from —H and —C(O)(CH₂)₀₋₂R¹⁶.
 8. A compound, or saltthereof, according to claim 1, wherein: R¹ is chosen from C₁ to C₂₀hydrocarbon, alkoxyalkyl, substituted arylalkyl, heteroarylalkyl, andsubstituted heterocyclalkyl; R² is chosen from

R⁵ is chosen from —H and alkyl; and R⁷ is chosen from —H, heterocyclyl,substituted alkyl, heteroarylsulfonamido, dialkylsulfonamido,

—NR⁸R⁹ wherein R⁹ is chosen from alkylcarbonyl, alkyl, substitutedalkyl, aryl and arylcarbonyl; R³ is chosen from a direct bond,

R⁴ is chosen from —H,

—C(S)NHR¹², —CHR¹³R¹⁴, —(O)NHR¹⁵ and —C(O)(CH₂)₀₋₂R¹⁶ wherein R¹⁰ is —H;R¹¹ is —H; R¹² is alkyl; R¹³ is —H; R¹⁴ is chosen from heteroaryl,substituted aryl and alkoxy substituted alkyl; R¹⁵ is chosen from aryland substituted aryl; and R¹⁶ is substituted aryl.
 9. A compound, orsalt thereof, according to claim 1, wherein; R¹⁴ is chosen from aryl,substituted aryl, heteroaryl, substituted alkyl and aryl substitutedalkyl.
 10. A compound, or salt thereof, according to claim 1, wherein:R¹ is heteroaryl; R² is chosen from halogen and

R³ is chosen from a direct bond,

R⁴ is chosen from —C(O)(CH₂)₀₋₂R¹⁶ and

11-14. (canceled)
 15. A pharmaceutical composition comprising as atherapeutic agent, a compound, or a prodrug or salt thereof, accordingto claim 1, and a pharmaceutically acceptable carrier. 16-18. (canceled)19. A compound, or salt thereof, according to claim 1, wherein X is—C(H)═, and X¹ and X² are each —N═.
 20. A compound, or salt thereof,according to claim 1, wherein X¹ is —C(H)═, and X and X² are each —N═.21. A compound, or salt thereof, according to claim 1, wherein X² is—C(H)═, and X and X¹ are each —N═.
 22. A compound, or a salt thereof,according to claim 1 wherein R¹ is chosen from C₁ to C₂₀ hydrocarbon,heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substitutedheterocyclylalkyl.
 23. A compound, or a salt thereof, according to claim1 wherein R³ is chosen from a direct bond; and R⁴ is

wherein R¹⁰ is —H; and R¹¹ is chosen from heteroaryl, substitutedheteroaryl and cycloalkyl.
 24. A compound, or a salt thereof, accordingto claim 1 wherein R¹ is chosen from heteroaryl, heteroarylalkyl,heterocyclylalkyl, and substituted heterocyclylalkyl; R³ is chosen froma direct bond; and R⁴ is

wherein R¹⁰ is —H; and R¹¹ is chosen from heteroaryl and substitutedheteroaryl.
 25. A compound, or a salt thereof, according to claim 1wherein R¹ is chosen from C₁ to C₂₀ hydrocarbon, alkoxyalkyl,heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;R² is chosen from substituted heteroaryl,

wherein R⁵ is chosen from H and alkyl; R⁶ is a direct bond; and R⁷ ischosen from heteroaryl and substituted heteroaryl R³ is chosen from adirect bond, and

wherein the left hand bond is the point of attachment to the ring andthe right hand bond is the point of attachment to R⁴; R⁴ is chosen fromhalogen, alkyl, heterocyclyl, alkylamino,

—C(O)NHR¹⁵ wherein R¹⁰ is chosen from H, alkyl and cycloalkyl; R¹¹ ischosen from H, C₁ to C₂₀ hydrocarbon and cycloalkyl; and R¹⁵ is chosenfrom H and lower alkyl; and Y is chosen from —H and lower alkyl.
 26. Acompound, or a salt thereof, according to any of claims 1, 19, 20, or21, wherein R¹ is chosen from —H, C₁ to C₂₀ hydrocarbon,aminocarbonylalkyl, alkoxyalkyl, substituted arylalkyl, heteroaryl,heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;R² is chosen from halogen, C₁ to C₂₀ hydrocarbon, hydroxy, heteroaryl,substituted heteroaryl, heterocyclyl, substituted heterocyclyl,

wherein R⁵ is chosen from —H, alkyl and substituted alkyl; R⁶ is chosenfrom a direct bond, alkyl, aryl, and heteroaryl; and R⁷ is chosen from—H, acyl, alkyl, substituted alkyl, alkoxycarbonyl, amidine, aryl,arylalkyl, heterocyclyl, heteroaryl, substituted heteroaryl, andsubstituted aryloxy; R³ is chosen from a direct bond,

wherein the left hand bond is the point of attachment to the ring andthe right hand bond is the point of attachment to R⁴; R⁴ is chosen from—H, halogen, alkyl, heterocyclyl, alkylamino, aminocarbonyl,

wherein R¹⁰ is chosen from —H, —OH, alkyl, cycloalkyl and substitutedcycloalkyl; R¹¹ is chosen from —H, —OH, —COOH, aryl, heteroaryl,substituted heteroaryl, aryl substituted alkyl, cycloalkyl, substitutedcycloalkyl, alkoxy, amonicarbonyl, and aminocarbonylalkyl; and Y ischosen from —H and lower alkyl.